Background Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays distinctive features than blood vasculature, and mechanisms underlying the formation of new lymphatic vessels during physiological and pathological processes are still poorly documented. Most studies on lymphatic vessel formation are focused on organism development rather than lymphangiogenic events occurring in adults. We have here studied lymphatic vessel formation in two in vivo models of pathological lymphangiogenesis (corneal assay and lymphangioma). These data have been confronted to those generated in the recently set up in vitro model of lymphatic ring assay. Ultrastructural analyses through Transmission Electron Microscopy (TEM) were performed to investigate tube morphogenesis, an important differentiating process observed during endothelial cell organization into capillary structures. [less ▲]

OBJECTIVE: To study whether Notch signaling, which regulates cell fate decisions and vessel morphogenesis, controls lymphatic development. METHODS AND RESULTS: In zebrafish embryos, sprouts from the axial vein have lymphangiogenic potential because they give rise to the first lymphatics. Knockdown of delta-like-4 (Dll4) or its receptors Notch-1b or Notch-6 in zebrafish impaired lymphangiogenesis. Dll4/Notch silencing reduced the number of sprouts producing the string of parchordal lymphangioblasts; instead, sprouts connecting to the intersomitic vessels were formed. At a later phase, Notch silencing impaired navigation of lymphatic intersomitic vessels along their arterial templates. CONCLUSIONS: These studies imply critical roles for Notch signaling in the formation and wiring of the lymphatic network. [less ▲]

in International Journal of Cancer = Journal International du Cancer (2009), 125(1), 34-42

The phloroglucinol derivative hyperforin, a major bioactive constituent of St. John's wort, is increasingly recognized as being able to regulate a variety of pathobiological processes and, thus, to ... [more ▼]

The phloroglucinol derivative hyperforin, a major bioactive constituent of St. John's wort, is increasingly recognized as being able to regulate a variety of pathobiological processes and, thus, to possess potential therapeutic properties. In the context of cancer, hyperforin induces the apoptosis of cancer cells, inhibits angiogenesis and suppresses metastasis formation. Here, we report a new pharmacological function of hyperforin and its stabilized derivative aristoforin, namely the suppression of lymphatic endothelial cell (LEC) growth and lymphangiogenesis. At concentrations less than 10 M, we found that these compounds induce cell cycle arrest of LECs, and at higher concentrations induce apoptosis. The loss of mitochondrial membrane potential and the activation of caspase-9 during the induction of apoptosis indicate that the intrinsic pathway of apoptosis is stimulated by these compounds, similar to the situation in tumor cells. In thoracic duct ring outgrowth assays, hyperforin and aristoforin both inhibited lymphangiogenesis, as evidenced by the suppression of lymphatic capillary outgrowth. In an in vivo animal model, both compounds were able to inhibit tumor-induced lymphangiogenesis. Together these data substantiate a new role for hyperforin and its derivatives as suppressors of lymphangiogenesis, and support their further investigation as potential anticancer drugs that target tumor growth and metastasis at multiple levels. [less ▲]